Acute Intermittent Porphyria Presenting with Posterior

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□ CASE REPORT □

Acute Intermittent Porphyria Presenting with PosteriorReversible Encephalopathy Syndrome, Accompanied

by Prolonged Vasoconstriction

Tadayuki Takata 1, Kodai Kume 2, Yohei Kokudo 3, Kazuyo Ikeda 1, Masaki Kamada 3,

Tetsuo Touge 4, Kazushi Deguchi 1 and Tsutomu Masaki 5

Abstract

A 20-year-old Japanese woman had an attack of acute intermittent porphyria (AIP). Magnetic resonance

imaging (MRI) revealed symmetrical lesions in the cerebrum and cerebellar hemisphere, corresponding to

posterior reversible encephalopathy syndrome (PRES). Our administration of heme arginate gradually im-

proved the clinical condition associated with AIP and the level of metabolite of nitric oxide (NO), which is a

vascular dilator. Repeated MRI and magnetic resonance angiography revealed exacerbated PRES, part of

which showed a small infarction, accompanied by progressive vasoconstriction. These findings suggest that

the recovery of NO by heme replacement alone is insufficient for preventing brain damage during an AIP at-

tack.

Key words: acute intermittent porphyria, posterior reversible encephalopathy syndrome, vasoconstriction,

ischemia, nitric oxide, nicardipine

(Intern Med 56: 713-717, 2017)(DOI: 10.2169/internalmedicine.56.7654)

Introduction

Acute intermittent porphyria (AIP) is an autosomal domi-

nant disorder caused by a deficiency of hydroxymethylbilane

synthase in heme biosynthesis (1, 2). The majority of pa-

tients with AIP show acute attacks that manifest as a combi-

nation of abdominal pain, mild mental symptoms, and auto-

nomic dysfunction (1). In addition, encephalopathy includ-

ing mental symptoms may derive from the brain lesions in

AIP, visualized as posterior reversible encephalopathy syn-

drome (PRES) (1).

Although the precise mechanism of encephalopathy in

AIP remains unknown, an initial event might be that a se-

vere heme deficiency during AIP acute attacks causes a lack

of nitric oxide synthase (NOS), which is a heme protein (3).

A decreased production of the major vascular dilator nitric

oxide (NO) (4) due to the lack of NOS is thought to elicit

vasoconstriction (5, 6). The hypoperfusion associated with

vasoconstriction might be involved in the incidence of vaso-

genic edema, which is a characteristic feature of

PRES (7, 8). In addition, prolonged vasoconstriction might

cause ischemic necrosis (9).

However, the relationship between vasoconstriction and

the level of NO has not been assessed during an acute attack

of AIP. Under these circumstances, we measured the con-

centration of nitrate ion (NO3-), which is an oxidized me-

tabolite of NO, in a patient with AIP presenting with pro-

longed vasoconstriction. To our knowledge, this is the first

report showing that NO seems to have little involvement in

prolonged vasoconstriction in AIP.

Case Report

A 20-year-old Japanese woman was admitted to a local

general hospital in October 2014 for severe abdominal pain

１Department of Neurology, Kagawa University Hospital, Japan, ２Department of General Internal Medicine, Kagawa University Hospital, Japan,３Department of Intractable Neurological Research, Kagawa University Faculty of Medicine, Japan, ４Department of Health Sciences, Kagawa

University Faculty of Medicine, Japan and ５Department of Gastroenterology, Kagawa University Hospital, Japan

Received for publication April 28, 2016; Accepted for publication July 6, 2016

Correspondence to Dr. Kazushi Deguchi, [email protected]

Intern Med 56: 713-717, 2017 DOI: 10.2169/internalmedicine.56.7654

714

Figure　1.　MRI findings obtained on the 5th day (A-C), 17th day (D-F), 31st day (G-I), and 51st day (J-L). The symmetric frontal, parietal, and occipital lesions observed on the 5th day were improved on the 17th day. These lesions showed high intensity on FLAIR images (A, D), slight high intensity on DWI (B, E), and high intensity on an ADC map (C, F) (arrowheads). Despite the recovery of the clinical condition, the brain lesions with the same characteristics as those observed earlier reappeared on the FLAIR image (G) and ADC map (I) on the 31st day (arrowheads). These areas were isointense on DWI (H). A part of the frontal lesions showed high intensity on DWI (H) and low intensity on an ADC map (I) (open arrowheads). These small lesions remained on FLAIR imaging (J) (open arrow-heads) but were obscure on the DWI (J) (open arrowheads) and ADC map (L).

A B C

D E F

G H I

J K L

that occurred intermittently over a 3-day period. She also

felt severe pain involving the entire body, especially in the

lumbar area. On the 4th day after the onset, she was put on

a mechanical ventilator because she experienced a general

convulsion followed by emotional lability. She developed

tachycardia and hypertension, which were intractable to

treatment.

On the 5th day after the abdominal pain’s onset, brain

magnetic resonance imaging (MRI) showed symmetric high-

intensity lesions in the frontal, parietal, and occipital lobes

and cerebellar hemispheres on fluid-attenuated inversion re-

covery (FLAIR) imaging. These lesions showed slight hy-

perintensity on diffusion-weighted imaging (DWI) and hy-

perintensity on an apparent diffusion coefficient (ADC) map

(Fig. 1). On the 7th day, magnetic resonance angiography

(MRA) provided ambiguous visualization suggesting vaso-

constriction in the bilateral posterior cerebral artery (PCA)

(Fig. 2). The patient was otherwise well aside from a diag-

nosis of allergic rhinitis. She was on no other medication

than dietary supplements, smoked approximately 10 ciga-


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Figure　2.　MRA findings obtained on the 7th day (A), 33rd day (B), and 51st day (C). The distal portion of the posterior cerebral artery (PCA) was visualized ambiguously on the 7th day. This abnormal finding spread to the proximal portion of the PCA and middle cerebral artery (MCA) on the 33rd day (arrowheads). As with the improvement in the MRI findings, the visualization of the MCA and PCA was nearly normalized on the 51st day.

A

B

C

rettes per day, and drank modestly. The date of her last

menstrual period was 4 weeks prior to her admission.

She was transferred to our hospital for further evaluation.

Her blood pressure was 176/93 mmHg, and her pulse was

113 beats/min with a regular rhythm, and this was refractory

to the administration of nicardipine (0.86 μg/kg/min). Her

blood test revealed increased levels as follows: white blood

cells, 14,180/μL; D-dimer, 6.5 μg/mL; C reactive protein,

1.26 mg/dL; total bilirubin, 4.7 mg/dL; direct bilirubin, 1.2

mg/dL; aspartate aminotransferase, 161 IU/L; alanine

aminotransferase, 57 IU/L; creatine kinase, 17,009 IU/L;

creatine kinase MB, 44 IU/L; and amylase, 183 IU/L. The

patient had hyponatremia (123 mEq/L) due to inappropriate

antidiuretic hormone secretion, which was later confirmed

by elevated plasma arginine vasopressin (20.1 pg/mL). The

results of a urinalysis were normal with the exception of

discoloration of the urine. The findings on a cerebrospinal

fluid examination was normal.

On the 8th day, she was weaned from ventilatory support.

She had mild weakness of the iliopsoas muscle and a de-

pressed deep tendon reflex. Nerve conduction studies

showed normal findings except for a low incidence of F

waves on the median, ulnar, and tibial nerves. Since the

characteristic clinical course is a good predictor of AIP, we

administered propranolol (0.01 mg/kg/h; the first choice for

treating hypertension and tachycardia of AIP) as a substitute

for nicardipine, the safety of which has not yet been estab-

lished (10, 11). A high-calorie and high-carbohydrate diet

with glucose was also administered (10).

On the 19th day, the patient’s levels of porphyrin precur-

sors in a urine sample proved to be extremely high as fol-

lows: porphobilinogen (PBG), 196.1 mg/day (normal value:

<2.0 mg/day) and δ-aminolevulinic acid (δ-ALA), 61.9 mg/

L (normal value: <5.0 mg/L). Although a genetic diagnosis

was not permitted by the patient’s family, the characteristic

symptoms and markedly increased level of porphyrin precur-

sors confirmed the diagnosis of AIP. With respect to the pa-

tient’s first-degree relatives, increased levels of urine δ-ALA

and PBG were revealed in her elder sister but not in her

mother. Her father refused the examination.

Following the daily intravenous administration of heme

arginate (3 mg/kg) from the 20th day to the 23rd day, the

patient’s elevated liver enzymes, hypertension, and tachycar-

dia moved gradually toward normal levels. The pain involv-

ing the entire body was also relieved. She has not suffered a

relapse of general convulsions even after the withdrawal of

anticonvulsant therapy. The deep tendon reflex returned to

normal. On the 52nd day, the patient had recovered inde-

pendent mobility and left the hospital.

Repeated MRI and MRA findings were as follows

(Fig. 1, 2): On the 17th day, the high-intensity lesions had

nearly disappeared with the exception of persistent partial

lesions in the parietal and occipital lobes. On the 31st day

(9 days after the end of the heme arginate administration),

FLAIR imaging unexpectedly showed the reappearance of

lesions in the frontal lobes as well as an increase in the size

of the lesions in the parietal and occipital lobes. Some of

the lesions in the bilateral frontal lobes located in the arte-

rial ‘watershed’ and ‘borderzone’ regions showed hyperin-

tensity on DWI and hypointensity on an ADC map. The le-

sions in the parietal to occipital lobes showed isointensity or

slight hyperintensity on DWI and high intensity on the ADC

map.

In addition, MRA revealed segmentally ambiguous visu-

alization in the proximal portion of the middle cerebral ar-

tery (MCA) and PCA. Although the segmental stenosis of

the MCA and PCA remained virtually unchanged on the

38th day, the relapsing lesions nearly disappeared except for

small lesions in the frontal and parietal lobes. On the 51st

day, the visualization of the MCA and PCA returned to

nearly normal.

To clarify whether the ambiguous visualization of the

MCA and PCA suggesting vasoconstriction was attributable

to decreased NO during the patient’s acute attack of AIP, we


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measured the level of serum nitrate ion (NO3-), which is an

oxidized metabolite of NO, before and after administration

of heme arginate. The level of NO3- measured by high-

performance liquid chromatography (12) was 12 μmol/L on

the 11th day, 21 μmol/L on the 17th day, and 35 μmol/L on

the 46th day (normal value: 10-71 μmol/L).

Discussion

Our patient had exclusively neurovisceral phenomena,

such as abdominal pain, autonomic dysfunction and mental

symptoms. In addition, the DWI and ADC map findings

suggested that the early cortical and subcortical lesions were

vasogenic edema, consistent with the typical neuroimaging

presentation of PRES (7, 13). Although these findings

prompted a differential diagnosis including hypertensive en-

cephalopathy, infection, and autoimmune diseases (7), the

markedly increased levels of urine PBG and δ-ALA indi-

cated a diagnosis of AIP (2). The prompt administration of

heme arginate (which replenishes the hepatic free heme

pool (10)) resulted in a gradual improvement in the patient’s

hypertension, tachycardia, and generalized pain. The MRI

lesions were improving but later showed exacerbation of

PRES, which was likely an ischemic change, at least in part,

accompanied by vasoconstriction expanded from the PCA to

the MCA over time.

PRES accompanied by vasoconstriction is not frequently

reported in AIP (14). Although the precise mechanism un-

derlying such findings remains unknown, there are several

hypotheses. Since hypertension during an acute attack of

AIP might exceed the autoregulation limit (mean arterial

pressure, 150-160 mmHg), hyperperfusion followed by

breakdown of the blood-brain barrier could lead to vaso-

genic edema, which is part of the histopathology of

PRES (7). In addition, severe heme deficiency during an

acute attack of AIP causes a lack of the heme protein

NOS (5). Since endothelial NOS (eNOS)-derived NO exerts

a vasodilating effect for maintaining the cerebral blood

flow (15), a lack of eNOS could be responsible for vasocon-

striction. In fact, the level of NO3- before administration of

heme arginate in our patient was at the low end of the nor-

mal range, suggesting a lack of eNOS.

However, these hypotheses are not likely to be applicable

in our patient’s case for several reasons. The hypertension

observed in our patient did not reach the level of failed au-

toregulation. Even after the normalization of her hyperten-

sion, the findings of PRES worsened rather than improved.

Although the infusion of heme arginate to replenish the he-

patic free heme pool (10) from the 20th day resulted in fur-

ther elevation of the level of NO3- on the 46th day, suggest-

ing the recovery of eNOS, both the PRES and the vasocon-

striction worsened. Alternatively, just as FK-506 and cy-

closporine A can injure endothelial cells directly (16), exces-

sive porphyrin precursors might cause endothelial cell dam-

age followed by a breakdown of the blood-brain barrier and

the release of potent vasoconstrictors, such as endothelin or

thromboxane (6).

It has been reported that protracted vasoconstriction might

be responsible for encephalopathy with a long clinical

course of recovery, and that it can cause ischemic cytotoxic

edema (9). Since our patient showed vasoconstriction that

continued until at least the 38th day, the relapsing PRES, a

part of which was the small ischemic lesions, might have

been due to the prolonged vasoconstriction. With the excep-

tion that our patient did not show an acute onset of severe

headache (i.e. a thunderclap headache), the clinical findings

were similar to the clinical presentation of reversible cere-

bral vasoconstriction syndromes (RCVS) in the following

aspects: (1) the reversibility of vasoconstriction within 12

weeks after onset; (2) evidence of brain infarction, particular

in the arterial ‘watershed’ and ‘borderzone’ regions; and (3)

the coexistence of changes consistent with PRES (17, 18).

For the alleviation of symptoms and rapid reversibility of

vascular abnormalities in RCVS, nicardipine with high lipo-

philicity seems to be considerably effective among the

calcium-channel blockers (19, 20). Indeed, our patient

showed recurring exacerbation of PRES accompanied by the

progression of vasoconstriction after the withdrawal of

nicardipine. However, because nicardipine is metabolized by

CYP3A4, which is a hemoprotein, a continuous nicardipine

infusion for preventing vasoconstriction might cause exacer-

bation of an AIP attack due to a heme deficiency. In addi-

tion, excessive decreases in blood pressure with nicardipine

might cause a watershed infarction in cerebral regions with

hypoperfusion by a severely constricted cerebral artery (17).

Therefore, nicardipine should be used cautiously under an

adequate replacement of heme arginate and blood pressure

monitoring.

In conclusion, PRES and vasoconstriction might be in-

volved in the expression of encephalopathy in AIP. The time

course of the present case as shown by MRI and MRA sug-

gested the development of a small infarction that was prob-

ably due to prolonged vasoconstriction. Although the ad-

ministration of heme arginate under supportive treatment in-

creased our patient’s level of NO3-, an oxidized metabolite

of NO, the vasoconstriction worsened rather than improved.

This finding suggests that the recovery of NO by heme re-

placement alone is insufficient for preventing brain damage.

In addition, the discontinuation of nicardipine might have

prolonged the vasoconstriction. These findings warrant fur-

ther research to reveal the precise mechanism underlying the

vasoconstriction and to establish the optimum nicardipine

regimen during AIP attacks.

The authors state that they have no Conflict of Interest (COI).

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Acute Intermittent Porphyria Presenting with Posterior